Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model
Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model
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DOI：
10.1007/s00280-006-0407-2
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发表时间：
2007-10-01
影响因子：
3
通讯作者：
Brem, Henry
中科院分区：
文献类型：
--
作者：
Brem, Sarah;Tyler, Betty;Brem, Henry
目的血小板减少症和白细胞减少症的剂量限制不良反应阻止了目前替莫唑胺（TMZ）给药方案的增加；因此，我们假设直接颅内给药TMZ会提高恶性胶质瘤动物模型的疗效。方法将替莫唑胺掺入生物可降解聚合物中，80 h后释放。F344大鼠颅内毒性评价，未达到最大耐受剂量。结果TMZ的体内生物分布表明，与口服TMZ相比，TMZ的颅内浓度增加了3倍。在啮齿动物胶质瘤模型中，用单一TMZ聚合物（50% w/w）治疗的动物的中位生存期为28天（与对照组相比P < 0.001，与口服治疗相比P < 0.001），而口服TMZ治疗的动物与对照组相比的中位生存期为22天（中位生存期为13天）。用两种TMZ聚合物（50% w/w）治疗的动物的中位生存期为92天（与对照组相比P < 0.001，与口服治疗相比P < 0.001）。颅内TMZ治疗组的长期幸存者（LTS）百分比从25%到37.5%不等；口服TMZ治疗组无LTS。与单独颅内TMZ治疗（中位生存期41天，LTS = 37.5%）或口服TMZ和XRT治疗（中位生存期43天，LTS = 38.9%）相比，接受放射治疗（XRT）和颅内TMZ治疗（中位生存期未达到，LTS = 87.5%）的动物的生存得到改善。结论与全身给药相比，局部给药TMZ能提高荷瘤动物的存活率。XRT联合颅内TMZ治疗没有引起额外的毒性，并进一步延长了生存期。
Purpose Dose-limiting adverse effects of thrombocytopenia and leukopenia prevent augmentation of current temozolomide (TMZ) dosing protocols; therefore, we hypothesized that the direct intracranial delivery of TMZ would lead to improved efficacy in an animal model of malignant glioma in an animal model.Methods Temozolomide was incorporated into biodegradable polymers and the active drug was released over 80 h. Intracranial toxicity was assessed in F344 rats and a maximally tolerated dose was not achieved.Results In vivo drug biodistribution demonstrated that intracranial concentrations of TMZ increased threefold compared with orally delivered TMZ. In a rodent glioma model, animals treated with a single TMZ polymer (50% w/w) had a median survival of 28 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment), whereas animals treated with oral TMZ had a median survival of 22 days compared to control animals (median survival of 13 days). Animals treated with two TMZ polymers (50% w/w) had a median survival of 92 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment). The percentage of long-term survivors (LTS) for groups receiving intracranial TMZ ranged from 25 to 37.5%; there were no LTS with oral TMZ treatment. Animals treated with radiation therapy (XRT) and intracranial TMZ (median survival not reached, LTS = 87.5%) demonstrated improved survival compared to those with intracranial TMZ alone (median survival, 41 days; LTS = 37.5%), or oral TMZ and XRT (median survival, 43 days, LTS = 38.9%).Conclusions The survival of tumor-bearing animals was improved with local delivery of TMZ compared with systemic administration. XRT in combination with intracranial TMZ did not cause additional toxicity and prolonged the survival even further.